Beta1-adrenergic and beta2-adrenergic receptors (betaAR) expressed in the heart and vasculature play key roles in regulating cardiac inotropy and chronotropy and represent targets for therapeutic agonists and antagonists in the treatment of heart failure. Heart failure exhibits extensive inter- individual variability in its clinical course and response to therapy. We hypothesize that betaAR polymorphisms, acting as disease modifiers, represent a substantial genetic component of this variability. Indeed, significant genetic variability in the structure of these receptors due to polymorphisms of their coding sequences has been identified. When expressed in transfected cells, a number of these polymorphic receptors display altered expression, agonist or antagonist binding affinities, activation of adenylyl cyclase, or agonist-promoted regulation. Having identified beta1AR and beta2AR polymorphisms of >1% in the population, and having determined their biochemical significance in cells, we now plan to focus on their relevance to heart failure. The broad their biochemical significance in cells, we plan to focus on their relevance to heart failure. The broad long-term objectives are thus to determine the disease modifying effects at the clinical, physiological and biochemical levels of betaAR polymorphisms in heart failure. Studies are designed to delineate their roles in: the development of left-ventricular hypertrophy and heart failure, the clinical prognosis and progression of failure, regulation of cardiovascular responsiveness to endogenous and exogenous activation, and modification of the clinical response to beta-blocker therapy. In addition, polymorphisms will be studied in gene targeted (tag- and-replace) mice so that more extensive biochemical and physiologic characterization during controlled cardiac modeling can be undertaken. These studies will delineate how genetic variability of betaAR alters cardiac function and impacts the clinical course and characteristics of heart failure. Such results may thus provide for important prognostic markers and lead to development of new heart failure treatments based on receptor genotype.